ABSTRACT Annually 40,000 die of unintentional trauma in USA, from potentially preventable complications after hemorrhagic shock. Guided damage control resuscitation (DCR) within the early golden hours improves hemostasis and metabolic homeostasis (Gonzalez, Ann Surg. 2016; 263:1051-9). Our long term vision for this proposal is to develop the knowledge infrastructure necessary to take DCR to the next level in 5-10 years to reduce post traumatic morbidity and mortality drastically (25%). The objective of this RM1 is to restrict thrombo inflammation without losing hemostasis or innate immune defense. The central hypothesis is that plasma can be tailored to achieve thrombo-inflammatory homeostasis. Our rationale is that plasma contains soluble, innate immune components that while perfectly normal can promote lethal thrombo-inflammation and organ injury in trauma patients. Our specific aims test the hypotheses that Trauma and Hemorrhagic shock (T/HS) Aim 1 Resuscitating hemorrhage-induced coagulopathy and immuno-inflammation: will explore the activation of thrombo-inflammatory serine protease cascades that increase vascular permeability, Aim 2 Allosteric modulation of fibrinolysis mediators: multi-domain Ser-proteases (plasmin interactome): will define and identify the released novels regulators of fibrinolysis into the plasma, Aim 3 LXR signaling and hemorrhagic shock rapidly alter the fibrinolytic phenotype: will define the involvement of liver nuclear responses regulating hemostasis in animals and Aim 4 Metabolic reprogramming drives deranged hemostatic and inflammatory responses after T/HS: will characterize the metabolites that perturb innate immunity. This contribution is significant because it provides animal and human data necessary for future FDA approvals while considering the role of sex differences. The proposed approaches are innovative on a number of areas: First, we evaluate complementopathy and kininopathy, which have not been well studied in the context of trauma, acidosis and coagulopathy. Secondly, we identify new regulators of plasmin. Thirdly, the switching of fibrinolysis from one phenotype to another through activation or antagonism of specific nuclear receptors is novel. Lastly, we have identified a number of metabolites that are associated with and induce organ injury/dysfunction, especially lung injury, and are investigating methods to inhibit their accumulation and effects. We have built a multidisciplinary team to study the scope of DCR since 2010. Over the years, we have engaged and supported experts in proteomics, metabolomics, and bioinformatics to analyze earliest patient plasma, discovering hemostatic phenotypes that predict outcomes. We have been amongst the first to test prehospital DCR in the field, and first to obtain detailed TEG and biochemistry of humans in post-traumatic shock. Over the years, we have refined optimal team dynamics 1) recruiting and sustaining suitable experts, 2) assigning responsibility according to specific expertise, and 3) building trust and resolving conflict by emphasizing personal growth.